{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T10:34:57Z","timestamp":1769164497067,"version":"3.49.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":564,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,18]],"date-time":"2020-04-18T00:00:00Z","timestamp":1587168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,18]],"date-time":"2020-04-18T00:00:00Z","timestamp":1587168000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Idiopathic pulmonary fibrosis is a lethal interstitial lung disease with unknown etiology, no cure, and few treatment options. Herein, a therapy option is presented that makes use of a heterogeneous population of lung cells, including progenitor cells and supporting cells lines, cultured in adherent and suspension conditions, the latter of which induces spontaneous spheroid formation. Within these spheroids, progenitor marker expression is augmented. The cells, called lung spheroid cells, are isolated from fibrotic lungs, expanded, and delivered in single cell suspensions into rat models of pulmonary fibrosis via tail-vein injections. Two bleomycin-induced fibrotic rat models are used; a syngeneic Wistar-Kyoto rat model, treated with syngeneic cells, and a xenogeneic nude rat model, treated with human cells. The first objective was to study the differences in fibrotic progression in the two rat models after bleomycin injury. Nude rat fibrosis formed quickly and extended for 30\u2009days with no self-resolution. Wistar-Kyoto rat fibrosis was more gradual and began to decrease in severity between days 14 and 30. The second goal was to find the minimum effective dose of cells that demonstrated safe and effective therapeutic value. The resultant minimum effective therapeutic dose, acquired from the nude rat model, was 3\u2009\u00d7\u2009106 human cells. Histological analysis revealed no evidence of tumorigenicity, increased local immunological activity in the lungs, or an increase in liver enzyme production. These data demonstrate the safety and efficacy of lung spheroid cells in their application as therapeutic agents for pulmonary fibrosis, as well as their potential for clinical translation.<\/jats:p>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Significance statement This study helps set the stage for the transition of this cellular therapy paradigm from rodent models to clinical trials in a number of ways. The transbronchial acquisition of the lung spheroid cells is a minimally invasive strategy suitable for the clinic and preferable to thoracoscopic alternatives; the doses used in this study are scalable, manufacturable, and comparable to currently existing clinical trial efforts targeting other lung diseases; and the intravenous route of administration used is applicable to clinical trials, as it presents an easy, quick, and patient-friendly way to administer the treatment.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/sctm.19-0167","type":"journal-article","created":{"date-parts":[[2020,4,18]],"date-time":"2020-04-18T07:57:50Z","timestamp":1587196670000},"page":"786-798","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A pre-investigational new drug study of lung spheroid cell therapy for treating pulmonary fibrosis"],"prefix":"10.1093","volume":"9","author":[{"given":"Jhon","family":"Cores","sequence":"first","affiliation":[{"name":"1 Joint Department of Biomedical Engineering University of North Carolina, and North Carolina State University, Chapel Hill and Raleigh, North Carolina, USA"},{"name":"2 Department of Molecular Biomedical Sciences and Comparative Medicine Institute North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phuong-Uyen C.","family":"Dinh","sequence":"additional","affiliation":[{"name":"2 Department of Molecular Biomedical Sciences and Comparative Medicine Institute North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor","family":"Hensley","sequence":"additional","affiliation":[{"name":"2 Department of Molecular Biomedical Sciences and Comparative Medicine Institute North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth B.","family":"Adler","sequence":"additional","affiliation":[{"name":"2 Department of Molecular Biomedical Sciences and Comparative Medicine Institute North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonard J.","family":"Lobo","sequence":"additional","affiliation":[{"name":"3 Division of Pulmonary Diseases and Critical Care Medicine University of North Carolina, Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Cheng","sequence":"additional","affiliation":[{"name":"1 Joint Department of Biomedical Engineering University of North Carolina, and North Carolina State University, Chapel Hill and Raleigh, North Carolina, USA"},{"name":"2 Department of Molecular Biomedical Sciences and Comparative Medicine Institute North Carolina State University, Raleigh, North 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